This application addresses the broad Challenge Area (15) Translational Science and specific Challenge Topic: 15-MH-104 Mouse models containing human genes implicated in mental disorders Differences in gene expression patterns between individuals are common, and it has been suggested that the polymorphisms responsible for these differences may account for the majority of human phenotypic variability. Gene expression is likely determined by the combined impact of environmental factors and inherited polymorphisms in regulatory regions of genes that modulate transcription or affect mRNA processing. Abundant polymorphisms in cis-acting sequences have been identified in genes implicated in psychiatric disorders. However, the elucidation of the contributions of these polymorphisms, both alone and when inherited in combination with polymorphisms at other loci, has been extremely difficult. The lack of progress in this area contrasts sharply with the progress that has been made in the evaluation of polymorphisms that alter protein structure. Mouse lines have been generated in which coding variants identified in patients have been introduced into the orthologous mouse gene using what are now standard genetic engineering techniques. These lines have provided important information regarding the functional importance of these polymorphisms. However, this method can rarely be used to study regulatory variants, as generally these polymorphisms are in regions that are less well conserved between mouse and human. In this application we propose a novel approach for evaluation of the functionality of polymorphisms in non-coding regions of genes believed to act in cis to regulate gene expression. We propose the generation of mouse lines in which the mouse ortholog of the human polymorphic gene is excised and then replaced with the syntenic human locus carrying either the disease associated or protective allele. The impact of the polymorphisms on gene expression during all stages of development, both during normal rearing and in response to imposed environmental stresses, can then be monitored. In addition, these lines will provide an opportunity to follow epigenetic changes at the human loci and to determine whether expression changes manifest as alterations in the behavior of the mouse. A large body of evidence indicates that both inherited and genetic components contribute to the risk for development of behavioral and psychological disorders. Numerous genetic studies have examined association between the development of these illnesses and the inheritance of alleles of genes in the serotonin and dopamine pathways. However, these studies are often inconclusive. This limits the ability of this information to be used in a clinical setting. In this application we propose a new method for validation of the function of variations in gene structure which are believed to confer risk for disease. Additionally, we propose methods for examination of the mechanism by which subtle differences in the primary structure of a gene can modify individuals'susceptibly for developing psychiatric and behavioral disorders. The mouse lines we propose to generate will help to define gene-gene interactions by allowing the study of multiple defined polymorphisms in mouse models related to these illnesses. This will help to define the risk conferred, not only by individual polymorphism but also the risk to the individual when multiple polymorphisms are inherited. We believe that these studies will, therefore, provide important information helpful in both the diagnosis and treatment of psychiatric illnesses.